04 May Metastatic Breast Cancer: Tumor Profiling by Liquid Biopsy Can Help Drive Therapy

MedicalResearch.com Interview with:

Rebecca Nagy

Rebecca Nagy
Vice President Medical Affairs
Guardant Health

 MedicalResearch.com: What is the background for this study?

Response: Hormone receptor positive (HR+) breast cancer comprises roughly 75% of all cancers of the  breast. While many of these cancers can be cured through multi-modality therapy, there remain many deaths due to metastatic spread to distant organs. These metastatic cancers are marked by their resilience in the face of potent targeted therapies and chemotherapies, with many tumors displaying an initial drug response followed by resistance.

Recently, genomic sequencing has identified recurrent, oncogenic alterations in HR+ metastatic breast cancer (MBC) with mutations in the catalytic alpha subunit of PI3K (PI3Kα, PIK3CA gene), in over 40% of cases. This has raised hopes for more durable disease control through precise inhibition of this driver oncogene.

The SOLAR-1 Phase III study of alpelisib combined with fulvestrant in PIK3CA-mutated HR+ MBC showed a markedly improved PFS over fulvestrant monotherapy but pervasive resistance nonetheless. To characterize the basis for such resistance to combination hormone plus PIK3CA targeted therapy, we conducted a detailed, longitudinal analysis of tumor and plasma circulating cell-freetumor DNA (ctDNA) among patients with HR+ MBC who participated in a phase I/II dose escalation study of alpelisib in combination with letrozole or exemestane. 

MedicalResearch.com: How does the Guardant360® liquid biopsy test improve the ability to detect significantly more instances of ESR1 genomic alterations, compared to tissue biopsy testing?

Response: In breast cancer, spatial and temporal intra-tumor heterogeneity is frequently observed, particularly in advanced disease. Individual needle biopsies may therefore not represent the full repertoire of tumor somatic alterations that influence clinical outcomes. Circulating tumor DNA (ctDNA) in blood can provide a more comprehensive picture of the tumor genome as ctDNA is derived from the pool of tumor sites shedding DNA. This was confirmed in the current study, as Guardant360 detected significantly more potential resistance alterations compared to tissue biopsy testing. These findings build upon the plasmaMATCH study results showing the importance of using a liquid biopsy test to conduct comprehensive genomic testing in metastatic breast cancer and to overcome the limitations of tissue to evaluate tumor heterogeneity. 

MedicalResearch.com: What are the main findings? 

Response: While the introduction of PI3K inhibitors in combination with endocrine therapy has made a significant difference in improving progression-free survival, the findings of this new study indicate the need for more comprehensive genomic profiling in hormone receptor-positive metastatic breast cancer patients. Testing more broadly beyond PIK3CA and with a liquid biopsy can help identify potential mechanisms of resistance to therapy and determine those patients most likely to respond to a PI3K inhibitor. In the current study, resistance to PIK3CA mutations was found in patients with PTEN  and ESR1 mutations. 

MedicalResearch.com: What should readers take away from your report?

Response: The importance of using a liquid biopsy test to conduct comprehensive genomic testing in metastatic breast cancer and to overcome the limitations of tissue to evaluate tumor heterogeneity. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work? 

Response: These results are the first to describe resistance mechanisms to alpelisib+fulvestrant in HR+ MBC, and may inform future studies as well as therapeutic drug development of 2nd generation PI3K inhibitors. 

Citation:

Razavi, P., Dickler, M.N., Shah, P.D. et al. Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors. Nat Cancer 1, 382–393 (2020). https://doi.org/10.1038/s43018-020-0047-1 

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Last Updated on May 4, 2020 by Marie Benz MD FAAD